I have been interested in this topic lately, and have seen questions asked about it in the past. I am researching the orthomolecular approach outlined by Dr. Carl Pfeiffer, and used at the Pfeiffer Treatment Center. I am going to have my histamine levels checked, and see if I am an under/over-methylator. The following article article is awesome and really interesting. It ties into many things we discuss here. Anyone please feel free to discuss, or comment on it. Thanks.

(The following information is taken from Dr. William Walsh's discussion on Safe Harbor's "Integrative Psychiatry" email list for professionals. To preserve Dr. Walsh's wealth of information, we have posted his comments here, with the notation of added commentary [with the date] as discussion goes on.)

Metabolic Types

About 7 years ago, I developed a classification system which subdivides the entire population into 26 metabolic types (Types A through Z). A small company in Illinois carried out a pilot study of this system (which they called "Bio-Logic") and provided compounded nutrients to more than 1,000 clients who paid for this service. The use of this system was limited to "wellness" clients who were free of serious mental problems. The company found that the results were generally very positive, with many loyal users. At least 26 types are needed to enable consideration of key factors including methylation, metal metabolism, glucose control, absorption, neurotransmitter synthesis, etc. For example, I am a Type L..... which means my genetic metabolic makeup results in a need for supplements emphasing methoinine, calcium, magnesium, zinc, and vitamins B-6, C and E...... and a need to completely AVOID supplements of folic acid, DMAE, choline, copper, etc. Proper typing requires identification of nutrients in overload (because of genetics) as well as nutrients in deficiency.

Mercury

The average amount of mercury we get from breathing is 1 mcg/day. The typical American diet provides another 15-20 mcg/day. If one eats tuna or other large ocean fish daily.... an intake of 60-80 mcg/day is possible.

For persons with normal metal metabolism (metallothionein, glutathione, etc), only 5% of ingested mercury gets into the bloodstream and less than 1% into the brain. Also, there are natural neuroprotective chemical factors in the brain which can sequester mercury & prevent damage.

All bets are off if a person has a serious metal-metabolism disorder......such persons may be hypersensitive to Hg. (Oct 30, 2003)

Metallothionein

The metallothionein (MT) theory seems more likely to be at the center of ASD. Children having a genetic weakness in MT activity would perforce have yeast overgrowth. MT kills candida, and helps regulate bacterial levels in the mucosa.

One-carbon (methyl) groups are involved in numerous important biochemical reactions in the body, including genetic expression, neurotransmitter synthesis and metabolism, etc. Methylation (more properly, the methyl/folate ratio) is a major factor in the rate-limiting step (the tetrahydrobiopterin reaction) in the synthesis of serotonin, dopamine, and norepinephrine in the brain. Undermethylated persons tend to be depleted in these 3 neurotransmitters, and the opposite is true for overmethylation.

The SAM cycle in which dietary methionine is converted to SAMe (the primary CH3 donor in the body), and then to homocysteine, is a dominant cascade of reactions in methylation and also is very important in production of glutathione, cysteine, and other aspects of sulfur chemistry.

Most persons with depression, oppositional defiant disorder, OCD, bipolar disorder, or schizophrenia exhibit a genetic abnormality in methylation..... which appears to be central to their illness. Carl Pfeiffer, MD, PhD of Princeton, NJ was a pioneer in this field. (Oct 3, 2003)

About 25 years ago, Dr. Carl Pfeiffer (Princeton, NJ) identified the condition he called "histapenia" or histamine deficiency. After studying the metabolism of more than 20,000 schizophrenics he learned that this "low histamine" syndrome was common in anxiety, panic disorders, and classical paranoid schizophrenia. His enormous biochemistry database revealed that most histapenics suffered from (1) copper overload and (2) deficiency of folic acid and/or B-12. More importantly, he found that aggressive therapy using folic acid, B-12, and B-3 usually produced dramatic improvements in these persons. Pfeiffer thought the improvements were largely due to elevating histamine levels in the body & brain.

Subsequent research has indicated that the improvements are due to normalizing the methyl/folate ratio. This ratio is important in the BH4 rate-controlling step in catecholamine synthesis (dopamine & norepinephrine). Also, methyl/folate abnormalities can impact genetic expression of many biochemicals. At any rate, too much methyl results in overproduction of DA and NE, and vice versa.

One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons)..... but are wonderful for high-histamine (undermethylated) persons. The reverse in true for histadelic (undermethylated) persons, who thrive on methionine, SAMe, Ca and Mg..... but get much worse if they take folates & B-12 which can increase methyl trapping.

I guess the bottom line is that undermethylated persons generally exhibit very elevated folate levels.... and these persons get worse if additional folate is given.

This is a fairly complex subject, and some of my medical staff are still struggling with the concept. However, they have the solace of knowing the clinical impact of methylation or folate therapy on persons with specific methylation/histamine disorders.

It's certainly true that whole blood histamine is compromised by AH treatments (including antigens and many psychiatric medications). We've gotten quite proficient in taking these factors into account. Fortunately, the ABC test doesn't suffer from this disadvantage. Also, the syndromes of over-methylation and under-methylation are well defined.... and a medical history & review of symptoms greatly aids the diagnosis. (Oct 6, 2003)

The generalization that perfume and other chemical sensitivities are associated with overmethylation, low blood histamine, and elevated norepinephaine... is exactly that...a general rule with many exceptions. However, the correlation seems to be above 90 percent in the case of perfume sensitivity. Whenever a patient enters our clinic wearing a mask to filter out inhalant chemicals, we immediately suspect the overmethylation syndrome. The chemical testing usually confirms this diagnosis, but there definitely are a few persons who have severe perfume sensitivity for other reasons. We've evaluated about 19,000 persons, including about 1500 with anxiety disorder or panic disorder. Hundreds of these patients reported sensitivity to perfumes. Nearly 90 percent of the perfume-sensitive group were overmethylated, and reported multiple chemical and food sensitivities. usually in the absence of seasonal inhalant allergies. Perfume sensitivity is a classic symptom of these high nonepinephaine persons, who usually respond beautifully to folate/B-12 therapy [1 Dec -03]

Inositol is especially helpful for undermethylated persons (for example most persons with OCD), but can cause negative side effects in those who are overmethylated. Since Inositol is one of the primary second messengers in neurotransmission, it's surprising is isn't more commonly used. It's especially useful in reducing anxiety and enhancing sleep.

To enhance sleep for a 160 lb person, we usually recommend 650 mg tablets, 1-3 as needed for sleep. Persons who have difficulty falling asleep should take it 30-60 minutes before sleep. Persons whose main problem is waking up in the middle of the night should take it at bedtime.

We've often given as much as 3-4 grams/day to undermethylated persons who respond beautifully to Inositol, and these persons take it morning, noon, and evening.

I once gave an invited presentation at a symposium at an APS annual meeting... in which data on megadoses (15-30 g) of Inositol were reported by another speaker. The volume of Inositol used seemed extreme to me, and would present daunting compliance problems. I believe such huge doses of Inositol are unnecessary, if methionine, calcium, B-6, and other nutrients to combat undermethylation are used. However, massive doses of Inositol might be needed if one tries to combat OCD with Inositol alone.

Regardless of the form of inositol, its use should be started as a trial, with close monitoring of patient. We've found that persons who achieve improved sleep after inositol are excellent candidates for taking it throughout the day also. I recommend you be alery for adverse side effects, especially with persons with severe anxiety or panic symptoms

Trichotillomania has been associated with OCD and undermethylation. If you can confirm the presence of undermethylation, the patient should benefit from (1) aggressive doses of l-methionine, calcium, magnesium, along with augmenting nutrients zinc, B-6, Inositol, Vitamin A & C and (2) strict avoidance of folic acid, choline, DMAE, and copper supplements

Aggressive methylation therapy can be very successful, but usually involves a very slow response. Typically, treatment with methionine, calcium, magnesium, B-6, etc requires about 2 months before the patient before any progress is evident --- and 6-12 months are required for all of the benefits to be attained. Please note that whole blood histamine is a marker for innate methylation tendency, but is not an indicator of wellness or the degree to which undermethylation has been overcome. Undermethylated patients can become quite well without their histamine lab results changing at all.

One way to speed up the process of recovery is to use SAMe supplements in the beginning. Undermethylated patients usually report nice progress after the first week or two. SAMe is quite expensive, and can be graduallyreplaced by methionine after a couple of months.

Nearly all severely undermethylated persons have low serotonin levels and present with a history of depression, internal anxiety, and OCD. Many have a history of perfectionism and high accomplishment in the early years.Unfortunately this population also has a tendency for non-compliance with any treatment.

The late and great Carl Pfeiffer would occasionally resort to use of the anti-histamines Benedryl or Dilantin in high-histamine persons who were slow to respond. Avoidance of folate supplements is essential for most undermethylated persons, an exception being autism

Some practitioners like to tinker with the SAM cycle to promote conversion of homocysteine to methionine, but this can deplete the cystathione pathway and result in deficiencies of glutathione, cysteine, etc. Some persons havea genetic enzyme weakness which can disrupt the SAM cycle

Undermethylated adults typically require 2,000 - 3,000 mg/day of methionine for several months to see good results. Also, augmenting nutrients such as calcium, magnesium, B-6, and zinc are essential.

TMG generally provides some benefits to undermethylated persons, but tends to make oxidative stress protections worse by diminishing the amount of homocysteine which converts via the cystathione pathway of the SAM cycle.TMG certainly is a promising nutrient for such persons, and adding some cysteine or glutathione can overcome the cystathione pathway deficit.

Personally, I believe the use of SAMe is the quickest way to help an undermethylated, high-histamine person.

Neurotransmitters

There are many possible causes of serotonin deficiency including severe B-6 deficiency, folate overload, undermethylation, malabsorption, tryptophan deficiency, weak activity of tetrahydrobiopterin, etc. It would help a lot if the underlying reason for the low serotonin activity could be identified. The rate-limiting BH4 step in serotonin synthesis deserves special attention.

Oxidative stress can also increase serotonin requirements. However, I believe that chelation for serotonin enhancement is a very bad idea. The patient might be better served by supplements of glutathione, selenium, metallothionein-promotion nutrients, etc, to reduce oxidative stresses.

Nutrient Therapy

Most mentally ill patients have a lousy diet, and aren't functional enough to achieve a major life-style change, such as fixing their diet. We've learned that the recipe for success is to first correct the primary chemical imbalance, and then fix the diet.

We've also learned to never attempt to take away their cigarettes, until AFTER they begin to respond to treatment..... for the same reason. Sometimes medical care (like politics) is the art of the possible.

We have major compliance problems with mentally-ill patients who hate medications. They become revulsed with swallowing capsules of all kinds, and it's hard to convince a paranoid patient that there really are nutrients inside.

Very few of our SZ or bipolar patients have any money or any insurance other than medicare. At present, about 65% of patients with private insurance receive coverage for our fees. PPO's pay about 20% of the time, but HMO's almost never cover our services. As a public charity, we provide financial assistance for most of our seriously mentally ill clients.

Compliance with nutrient therapy is a big problem even in cases of 100% recovery. Eventually a patient will wonder if they really need to continue swallowing those capsules daily, and may stop for a few days. They don't realize that it may take several weeks/months for their brain chemistry to revert to the original condition..... Often they are ok for about a month and then relapse. Nutrient therapy is much slower in response than medications.

We learned that best results are achieved if the patient continues their medication(s), if any, during the first few months of treatment. After the patient is significantly improved, we suggest that the medication be slowly reduced "to determine the optimum dosage of the medication". Many psychiatrists will agree to this..... but often are astonished to discover that the patient is just fine with zero medication.

Medications can usually take away a patient's psychosis, but the resulting over-sedation and "zombie-like" condition is repulsive to many. (March 18, 2003)

We have corrected the disordered chemistry of hundreds of conduct disorder & ODD children & teens. We've learned that the older patients have a rotten self-image and terrible social habits, even if the original cause of the behavior disorder is eliminated. They usually profit greatly from quality counseling, once the chemistry is fixed. (1 Jan, 2003)

In my experience, counseling is often unsuccessful until the "edge" of the OCD tendency is overcome with methylation therapy..... but thereafter quality counseling can be helpful. (21 Dec, 2002)

My clinic has used inositol with thousands of patients & learned the following:

A) Inositol is usually very helpful for UNDERMETHYLATED, HIGH HISTAMINE patients. This includes nearly every OCD patient we have seen. Inositol usually provides calming throughout the day and ability to settle down to sleep at night, for these patients.

B) On the other hand, OVERMETHYLATED patients usually derive little or no benefit from Inositol, and may experience very nasty side effects from it.

C) Although a couple thousand milligrams may be needed to do the job & the tablets are often quite large, Inositol has the great advantage of being palatable..... Many of our patients chew it before swallowing, and report it "doesn't taste bad at all".

I'm quite surprised that Inositol isn't more popular due to its effectiveness and its role as a major "second messinger" in neurotransmission.Anorexia and bulimia

We have found that nearly all anorexic and/or bulemic patients are very undermethylated, low serotonin persons. Most of then respond very well, albeit slowly, to aggressive doses of methionine, Vitamin B-6, and calcium. A positive response can usually be achieved more rapidly with SAMe. In severe cases we often start with SAMe to get a quick improvement, and than gradually convery to methionine/B-6/calcium.

I certainly agree that a lousy food choices can aggravate an eating disorder, and might even trigger it in a person with a tendency for OCD and delusional thinking. An excellent dietary & nutritional program is an important component of success for these persons. (7 Jan, 2003)

In my experience, most anorexics are perfectionistic, obsessive-compulsive, high-histamine, low serotonin persons. Most have a history of high accomplishment in school and were never discipline problems. Most anorexics also have a history of being overweight, at least in their eyes. When they begin to diet, their OCD takes over and they go to great extremes. Also, when these emaciated skeletons of people look in the mirror, they tell me that all they see is FAT. It seems to involve a nasty combination of obsessive/compulsive disorder plus delusional thinking. I've never noticed a correlation with lousy diets. The anorexic I know best at present is a dedicated nutritionist/dietician..... who eats only the finest nutrient-dense whole foods. Her condition is still serious. (Jan, 2003)

I've observed that most anorexic and bulemic patients benefit greatly from a combination of biochemical therapy and counseling/psychotherapy. (30 Dec, 2002)

I've researched the biochemistry of hundreds of OCD patients, many of whom had comorbidity for schizo-affective disorder or delusional disorder. Typical characteristics for this patient population include undermethylation, weak functioning of the BH4 rate-limiting steps in synthesis of serotonin, and dopamine, low calcium levels, excessive folate levels, and high oxidative stress. (Aug 4, 2003)

Other helpful nutrients for OCD are methionine, calcium and magnesium...... since virtually all OCD patients are undermethylated, low-serotonin persons. (Aug 8, 2003)

Inositol is especially helpful for undermethylated persons (for example most persons with OCD), but can cause negative side effects in those who are overmethylated. Since Inositol is one of the primary second messengers in neurotransmission, it's surprising is isn't more commonly used. It's especially useful in reducing anxiety and enhancing sleep.

To enhance sleep for a 160 lb person, we usually recommend 650 mg tablets, 1-3 as needed for sleep. Persons who have difficulty falling asleep should take it 30-60 minutes before sleep. Persons whose main problem is waking up in the middle of the night should take it at bedtime.

We've often given as much as 3-4 grams/day to undermethylated persons who respond beautifully to Inositol, and these persons take it morning, noon, and evening.

I once gave an invited presentation at a symposium at an APS annual meeting... in which data on megadoses (15-30 g) of Inositol were reported by another speaker. The volume of Inositol used seemed extreme to me, and would present daunting compliance problems. I believe such huge doses of Inositol are unnecessary, if methionine, calcium, B-6, and other nutrients to combat undermethylation are used. However, massive doses of Inositol might be needed if one tries to combat OCD with Inositol alone.

A word of caution --- Manganese supplements tend to aggravate Tourette's Syndrome, and can also worsen the symptoms of OCD.

Trichotillomania has been associated with OCD and undermethylation. If you can confirm the presence of undermethylation, the patient should benefit from (1) aggressive doses of l-methionine, calcium, magnesium, along with augmenting nutrients zinc, B-6, Inositol, Vitamin A & C and (2) strict avoidance of folic acid, choline, DMAE, and copper supplements

Oxidative Stress

It's essential of course for digestive exzyme preparations (such as AbsorbAid) to survive stomach acid. However, this won't help if there is too much oxidative stress in the gut, as this can wipe out many of the key enzymes (such as DPP-IV). Oxidative stresses often are the cause of the malabsorption or maldigestion problems..... Sending in more enzymes can have limited effect in this case. It's a little bit like Pickett's charge in the Civil War: The new soldiers are killed off as soon as they enter the fray.

We find that zinc therapy and metallothionein-promotion therapy can be effective in easing oxidative stress in the G.I. tract and overcoming these problems.

Tests for plasma zinc, serum copper and serum ceruloplasmin can give a good indication of "metal" oxidative stress. A Cu/Zn ratio greater than 1.20 or an excessive amount of "unbound" copper..... that is, copper not bound to ceruloplasmin..... are indicators of excessive free radical metal ions which can suppress or destroy many digestive enzymes, cause diarrhea, digestive pain, maldigestion, malabsorption and multiple food sensitivities. The levels will be abnormal in the presence of toxic overloads of mercury, cadmium, lead, antimony, etc. A hair analysis for the metals can provide some information also.(March 6, 2003)

Biochemical individuality is the key since there are many different biochemical abnormalities which may be at the root of the disorder....and each requires different clinical intervention.

However, one common thread which is present in most cases of SZ, ODD, ADHD, etc...... is excessive oxidative stress. As a result most of these patients exhibit high-normal (or worse) levels of toxic elements. The toxic metals are not the cause of the condition, but rather a consequence of genetic abnormality in metal-metabolism. Use of oral chelation is a short-term solution since DMSA, DMPS, etc do nothing to prevent lead, cadmium, mercury, etc from accumulating in the body again due to natural environmental exposures. Personally, I greatly favor metallothionein promotion therapy which can provide enduring benefits.

Many patients report a very nice improvement within a few days after oral chelation..... the improved symptoms usually last about 3 weeks, after which most patients return to the original state. Most practitioners who supervise chelation focus on driving toxic metals out of the body. However, I'm convinced that the improved symptoms are really due to the fact that the patients had severe oxidative stress, and DMSA, DMPS, etc are terrific antioxidants. I've known of many cases of autistic children who improve dramatically after DMSA, but lose the benefits in a very short time...... The same scenario may occur after more than 1.5 years of chelation. This clearly indicates that the improvements achieved were due to antioxidative benefits, rather than exit of toxic metals.

Occasionally we encounter a patient who has actually been severely poisoned by a toxic metal, and chelation is the first option. However, this is really quite rare. (Aug 4, 2003)

Another factor to consider is the high incidence of oxidative stress in the G.I. tract. This environment can destroy key digestive enzymes such as DPP-IV (needed to break down casein & gluten)..... This condition is especially common in autism-spectrum disorders.

Failure to correct the oxidative stress would doom supplemented enzymes to an early death. The result can be similar to Pickett's Charge at the battle of Gettysburg.... The digestive enzymes are mowed down as soon as they enter the G.I. tract.

On the other hand, amino acid supplements can be quite helpful, even if digestive enzymes are absent. The reason is that the enzymes act to cleave (break down) proteins into the individual amino acids before the AA's can be absorbed. "Free-form" amino acids need no further digestion or conversion..... They are already completely broken down to the form needed for efficient absorption.

Of course, proper enzymatic action is needed for effective processing of dietary protein and other foods, a requisite for good G.I. tract health. (Aug 20, 2003)

The casein-free, gluten-free diet often results in rapid striking improvements. However, nutritional supplements which overcome G.I. tract oxidative stress can make the CF/GF diet unnecessary.

Normalization of zinc, metallothionein, and glutathione in the G.I. tract isn't difficult to accomplish. It's a lot easier to take a couple of capsules daily than this difficult diet. It takes about 6-8 weeks for the G.I. tract to get "fixed" using this therapy.

We've had many patients who were extremely sensitive to dairy and wheat.... and did marvelously after the CF/GF diet. Many of these same patients completely lost their sensitivity to casein and gluten after the antioxidant supplementation..... and now can eat a normal diet without a problem. (Aug 21, 2003)

It's becoming increasingly clear that oxidative stress has an important role in mental illness. Since psychic stress increases oxidative stress in the brain, sudden easing of emotional traumae would be expected to have a direct and beneficial chemical effect on the brain.

It's true that mercury can be devastating to the brain and chelation cleans up peripheral mercury. However, most of us have a very effective system to protect us from mercury, namely glutathione & metallothionein in intestinal barriers, liver, blood/brain barrier, and the brain itself. Chelation to remove metals should be helpful only (a) in cases involving massive poisoning by heavy metals, or (b) in cases in which the normal protective systems fail to function properly. However, chelation can provide 2-3 weeks of benefits just from the antioxidant effect, whether or not there are nasty metals present.

Did you know that nearly all psychiatric medications are powerful anti-oxidants? I don't think this is a coincidence.

Paranoia

Paranoia is a symptom rather than a specific disease condition, and is associated with a number of biochemical imbalances. First of all, it is clear that paranoia generally involves a genetic predisposition. In my experience paranoia usually involves either highly elevated norepinephrine or diminished GABA levels. The recipe for paranoid schizophrenia is (1) overproduction of dopamine due to an innate tendency for overmethylation, (2) excessive conversion of dopamine to norepinephrine due to high copper levels, and (3) depressed levels of GABA (which tends to quench the paranoia & anxiety associated with elevated norepinaphrine. The patients are usually afflicted with multiple medications which can provide some relief, albeit with very unpleasant side effects. Complementary medicine techniques to balance body/brain chemistry may involve therapies using folates, zinc, manganese, and vitamins B-3, B-6, C, and E and can be very successful This treatment should be individualized to reflect the individual's array of chemical imbalances.... for best results. In many cases paranoia is exacerbated by estrogen therapy, environmental sources of copper, well-intentioned (but wrong) vitamin/mineral supplements, and/or chelation therapy. For females, paranoia tends to flare up during hormonal events including puberty, childbirth, and menopause. (Feb 10, 2003)

Placebo effect

I believe there are 4 major factors at work here: (1) improvements resulting from environmental changes, (2) true placebo effects in which a caring practitioner supplies hope, encouragement, and a positive attitude to the patient, (3) a Hawthorne effect in which the family and medical practitioners are giving attention & are monitoring the patient, and (4) cycles of improvement and relapse which are so strong that they overwhelm the therapies. (30 Dec, 2002)

Post Partum Depression

We have seen more than 3,500 persons with clinical depression including several hundred with a history of post-partum depression. Most PPD females exhibit a copper overload and zinc deficiency. Most PPD females report major improvement after nutrient therapy aimed at balancing Cu & Zn levels. Most normals have Cu/Zn ratios in the 0.75 to 1.15 range, whereas most PPD females exhibit a Cu/Zn ratio in the 1.5 to 2.0 range. The cause appears to be a genetic weakness in regulation of Cu & Zn which may involve weak functioning of the metallothionein/glutathione system.

Pregnancy

Depression, anxiety, panic episodes, and paranoia in pregnancy are often caused by an inborn inability to regulate copper and zinc in the body. During pregnancy, a woman's blood copper level more than doubles..... in order to provide sufficient copper to the fetus to support angiogenesis. Persons who have a genetic tendency for copper overload get into real trouble during and immediately after pregnancy since elevated Cu levels in blood result in diminished dopamine and elevated norepinephrine in the brain. This is a recipe for panic attacks, depression, etc.

I suggest a blood serum test for copper and a plasma test for zinc. If the levels are severely abnormal, there are natural treatments which can decisively correct the problem. The first step is to discontinue pre-natal vitamin supplements that contain copper. We've guided dozens of anxiety/panic/depression prone women through pregnancies, but one must be careful to avoid aggressive therapies (including natural ones) which might adversely affect the fetus. (Sep 8, 2003)

A published article of interest is one by John Crayton (research psychiatrist, then at U. of Chicago). Crayton measured dendrite populations with and without psychiatric medication. He found that psychiatric medication (I think he focused on Prolixin) caused a proliferation of dendrites on peripheral neurons. This, of course, is a permanent change..... and possibly the cause of Tardive Dyskinesia. This article received very little attention, despite its striking finding..... namely, permanent damage caused by psychiatric medication. (Sep 2, 2003)

Pyrrole Disorder

Omega 3s can worsen mental symptoms in bipolar or schizophrenic patients.... if they have a pyrrole disorder. This phenotype is dramatically short of arachidonic acid & giving omega 3 oils aggravates the situation since omega 3 and omega 6 EFA's are in competition for delta 5,6 desaturases. We use red blood cell membrane analysis for EFA'sif we suspect this problem.

Pyroluric mental patients will usually get worse if given fish oils, DHA, EPA, etc. They thrive on Primrose Oil, a good source of AA and other omega 6s. (June 23, 2003)

Most persons with pyroluria respond very quickly to the B-6, Zn, C, E therapy..... Major improvements are often seen by the 2nd day, and almost always by the end of the first week. The exceptions are: (1) persons with severe mental illness (schizophrenia or bipolar), (2) persons with other significant chemical imbalances, and (3) patients with a major malabsorptive condition. When pyroluria is diagnosed along with another chemical imbalance, I like to track a patient during the first 6-8 weeks to determine which is the dominant imbalance. If major improvement occurs immediately, it's because pyroluria has been corrected. Some patients report a nice early improvement followed by a plateau, and then another advance.

Schizophrenic and bipolar pyrolurics usually report some progress after a few weeks, but it may take 3-6 months to get to steady state. The biggest problem with the Kp analysis is getting a proper sample to the lab. The kryptopyrrole molecule is unstable and will disappear rapidly at room temperature or if exposed to bright light. The urine sample must be placed in a freezer immediately after acquisition. Kp can be lost in the freezer if the temperature isn't well below 32 degrees F. We've also learned that exposure to bright light results in breakdown of the Kp molecule. Finally, the sample must be maintained in a frozen condition during shipment. I would greatly suspect any Kp value below 3.0. Usually this means the sample didn't get to the lab in proper condition.

With respect to reference levels: We consider a healthy level to be between 4-8 mcg/dL. We consider persons between 10 and 20 to have mild pyroluria, and a good response to treatment is usually reported. Persons exhibiting 20 to 50 mcg/dL have moderate pyroluria, which can be a devastating condition. Persons above 50 mcg/dL have severe pyroluria.

Longitudinal testing of pyrolurics has shown that major variations can occur during a day. For example, Arthur Shawcross (famous NY serial killer) had levels ranging from 35 to 203, with higher levels observed during stressful periods in prison. However, he always tested as pyroluric in multiple tests. Stresses, illnesses, injury, etc can be expected to elevate Kp levels. Medical history and review of symptoms are vital to this diagnosis.

The major challenge in differential diagnosis of pyroluria is the similarity in symptoms between pyroluria and overmethylation (low blood histamine). Another problem is that symptoms of pyroluria are greatly muted in undermethylated, obsessive/compulsive persons. These persons may be high achievers, with great internal tension..... Persons with pyroluria alone tend to underachieve, partly because of a poor short term memory and associated reading problems. (Nov 10, 2003)

We've obtained hair Zn and plasma Zn levels (simultaneously) about 40,000 times. Low hair zinc correlates beautifully with low plasma levels. However, very elevated Zn in hair nearly always means Zn deficiency and loss plasma Zn levels. Most of the time this involves a Pyrrole disorder which results in very high Zn excretion in urine (and hair). In a healthy person without metal-metabolism problem, only about 4 percent of excreted Zn leaves through the kidneys. [28 Nov 03]

Paradox- This is a fascinating write-up. I can't believe others have not commented on it. Though I know that the subject of methylation has ben discussed here before.

I've been learning more and more about methylation recently and it's importance is just unquestionable IMO. I have a history of depression that I can trace back to about the age of 7-8. I didn't realize it until I was 25, after I was put on an SSRI, everything went down hill. Since then I have been on a journey to try and figure this thing out. I think that addresing methylation is important for me now.

I think that I am an undermethylator, because I responded wel to anti-histamine medication and another thing that I deal with is OCD. I'm sure I have a metal problem with mercury and consequently oxidative stress.

How can I be sure that I am indeed an undermethylator? Is there somekind of test that I can take?

Also, what is the standard protocol for treating undermethylation/overmethylation? In the write-up Inositol is suggested in high dosages. What would be a protocol that I can try once I confim my methylation status? Any help would be greatly appreciated.

I think that more posters should read this write-up. Especially those of us that have a history, or might have psycological issues. I think that addressing that should be a priority to hair, just IMO. A quote from the write-up:

Most mentally ill patients have a lousy diet, and aren't functional enough to achieve a major life-style change, such as fixing their diet. We've learned that the recipe for success is to first correct the primary chemical imbalance, and then fix the diet.

We've also learned to never attempt to take away their cigarettes, until AFTER they begin to respond to treatment..... for the same reason. Sometimes medical care (like politics) is the art of the possible.

I posted this a while back now. I tried for a while to figure out what category I fit into, after buying the book- Depression Free Naturally- which covers the same stuff. This is all based on Orthomolecular psychiatry. I just never could fit into over or under methylation symptomatically, and tried the approach for both. I have lab confirmed low cortisol and dhea, so maybe my methylation is fine, but I doubt that. My issue was that I was coming off pharmaceuticals, so I couldn't figure out what these natural things were doing for me. I was also taking so many pills and powders that there would have been no way to know. Just the top 6 involves quite a few pills a day as it is. I was taking handfuls for a while. Probably the only way I could ever benefit from this would be to go somewhere where they could run all the required labs so that I wasn't driving myself crazy trying to figure it out myself.

The histamine level for instance is supposed to be inversely related to methylation. I used a different lab than the one in the book, with a different procedure (labcorp I think)and my low histamine result actually said on it something like "Low histamine can also indicate extremely high histamine because of the method of testing". It was ridiculous and after taking SAM-E and getting really bad, I just couldn't deal with the whole thing anymore.

Sorry that's not encouraging, but it's only my experience. YMMV. When I filled out the symptom questions in the book, I could have fit almost everything. I mean I had symptoms of both Omega 3 and Omega 6 deficiency, and symptoms of high and low histamine. I just couldn't force myself into one of the boxes no matter how much I wanted to (and I did want to!). I'm avoiding b12 at one point because it's supposed to be bad if you have OCD (undermethylator/high histamine) and my b12 lab comes back on the low-normal side. THere was a notation on my b12 lab as well: "b12 levels below 400 can result in severe psychiatric symptoms." My level was 400.

BTW- I did send out the lab for the Pyroluria which I really thought I had, and it came back normal.

Paradox wrote:I posted this a while back now. I tried for a while to figure out what category I fit into, after buying the book- Depression Free Naturally- which covers the same stuff. This is all based on Orthomolecular psychiatry. I just never could fit into over or under methylation symptomatically, and tried the approach for both. I have lab confirmed low cortisol and dhea, so maybe my methylation is fine, but I doubt that. My issue was that I was coming off pharmaceuticals, so I couldn't figure out what these natural things were doing for me. I was also taking so many pills and powders that there would have been no way to know. Just the top 6 involves quite a few pills a day as it is. I was taking handfuls for a while. Probably the only way I could ever benefit from this would be to go somewhere where they could run all the required labs so that I wasn't driving myself crazy trying to figure it out myself.

The histamine level for instance is supposed to be inversely related to methylation. I used a different lab than the one in the book, with a different procedure (labcorp I think)and my low histamine result actually said on it something like "Low histamine can also indicate extremely high histamine because of the method of testing". It was ridiculous and after taking SAM-E and getting really bad, I just couldn't deal with the whole thing anymore.

Sorry that's not encouraging, but it's only my experience. YMMV. When I filled out the symptom questions in the book, I could have fit almost everything. I mean I had symptoms of both Omega 3 and Omega 6 deficiency, and symptoms of high and low histamine. I just couldn't force myself into one of the boxes no matter how much I wanted to (and I did want to!). I'm avoiding b12 at one point because it's supposed to be bad if you have OCD (undermethylator/high histamine) and my b12 lab comes back on the low-normal side. THere was a notation on my b12 lab as well: "b12 levels below 400 can result in severe psychiatric symptoms." My level was 400.

BTW- I did send out the lab for the Pyroluria which I really thought I had, and it came back normal.

Paradox- Thanks for sharing. I understand your frustration and applaud you for researching and experimenting.

I do have symptoms of both under and over methylation. I'm reading that the best way to test for this is a urine amino acid test. Right now I am feeling desperate, yet optimistic, to get this under control. I'm almost sold on being an under methylator based on my positive response to anti-histamine medications, and as you mentioned, the histamine levels are supposed to be inversely related to methylation.

Yesterday I read up on obsessive compulsive disorder, after reading that OCD is strongly correlated with undermethylation, and I saw that I have almost all of those symptoms, albeit mild--not too crazy I think.

At this point I will just go off of these symptoms and try a few things out.

Here is another fascinating read IMO, that I found yesterday. It is a great followup to the one you posted. I encourage you and others to read it if you haven't already.

Note that the author mentions a discrepancy with certain statements from Pfeiffer's work--a contradiction. This being that the methylation pre-cursors folate and B-12 are separated from the other pre-cursors in terms of what side of the spectrum they benefit, over or under. Why is that? It did not make sense to me either when I read the piece in the first post. It is a great question, I mean, why would folate and B-12, two pre-cursors to methylation be contraindicated in people who are undermethylators? So perhaps, this is some kind of an error on the part of Pfeiffer and co. in their publication or otherwise.

Also, it looks like B-3 uses up methyl groups. So high dose B-3 is a no-no for undermethylators and could impeded benefits even when trying to correct methylation. Inversly, B-3 is good for overmethylators as it helps reduce the methyl groups.

Something else that I read in a separate instance is that nitric oxide promotors could be bad for undermethylators as they further reduce methylation. I have to read more on that, maybe look up some studies.

And, also, note the importance of enzymes/digestion.

It's all a big complex intertwined process.

Hope this helps. Enjoy!

MethylationCopyright August 2002. Kd. last updated 8.25.05This is a discussion which tries to outline the points of methylation and establish some relationships that will result in the practical application of the information. Special thanks to andrew who contributed many links and much understanding to this discussion.

This link has a nice picture of what this process looks like. You may want to refer to it often during the following discussion. http://www.nutriwest.com/articles/homovmsm.htm

The issue of a person being an under or over methylator can be confusing. It may not be one of the all time critically defining issues, but it may help in the general sense. Several common supplements often recommended for those with autism spectrum conditions are involved in this process (this is just one of the processes these supplements may help with).

A "methyl" group is simply one carbon connected to three hydrogen atoms. It may be written as CH3 with the 3 being a subscript.

"Methylation" is not just one specific reaction. There are hundreds of "methylation" reactions in the body. Methylation is simply the adding or removal of the methyl group to a compound or other element.

So why do we care about methylation at all? In general, when some compounds receive a methyl group, this "starts" a reaction (such as turning a gene on or activating an enzyme). When the methyl group is "lost" or removed, the reaction stops (or a gene is turned off or the enzyme is deactivated). Some of the more relevant methylation reactions would be:1. getting methyl groups "turns on" detox reactions that detox the body of chemicals, including phenols. So if you are phenol sensitive, and you increase your methylation, then theoretically your body can process more phenols and you can eat fruits without enzymes!

2. getting methyl groups "turns on" serotonin, and thus melatonin, production. Therefore, if you are a under-methylator, you can increase your methylation and have higher more appropriate levels of serotonin and melatonin. This means you may not have to take SSRIs, or may have improved sleep.

3. if you are an over-methylator you can take certain supplements to decrease methylation and perhaps turn off reactions that need to be off. This may decrease aggression or hyperness, for example.

This is the general idea. To what extent this actually works in real life for any individual is back to "every one is different." But this is one thing that the Pfeiffer Treatment Center really looks at. I hope this explanation helps.

Something to note is that everyone is not EITHER an over OR under methylator. There are more groups than that, and you may be just fine in regards to methylation. Even if the Pfeiffer statistic is exactly correct when they say 45% are under-methylators and 15% are over-methylators, that totals 60%, so almost half the people are neither.

Where this MIGHT be helpful would be in picking supplements. So someone may do badly on the high B6 protocol. If that person does badly on TMG or DMG too this may be a clue that they will do poorly on ALL the methylation precursors so they can steer clear of that group in high doses. And vice versa, if they did really well with one, then they may also do well with others in the group. Of course, they may not see additional benefit if the methylation process is fixed with the first supplement, but it is something that might help a person know why they or their child is consistently doing well or poorly with a group of supplements.

Is there any evidence to support this? Well, I am looking at the ARI data gathered from over 18,500 parent surveys. Let's say Pfeiffer is exactly correct and under-methylators are about 45% of the "autism" population. These are the values for the precursors for methylation:- calcium 39% saw improvement- DMG 43% saw improvement- Folic acid 44% saw improvement- B6/mag (both of these are precursors) 46% saw improvement- Zinc 43% saw improvement

So if you look at any of the precursors, really, most are around that 45% mark of under-methylators (calcium was a little low, but it is a supporting element). So we have a mark of consistency here. SAMe, methionine, and B12 were not choices. What this does NOT point out is which came first. Was zinc low for some reason not related to methylation and because it was low, methylation dropped? or are you a genetically low-methylator to begin with and do not utilize the nutrients at hand well? Or was folic acid the bottle-neck? or magnesium deficiency? Or an injured gut which cannot adequately absorb any of the nutrients? or....

This is how I see it, just as a general guideline that may be helpful, not a cast in stone type of thing.

Where do SAMe, methionine, folate, depression, and all that other stuff fit in?

Please refer to the diagram at the link given:http://www.nutriwest.com/articles/homovmsm.htm

The basic cycle works like this. Methionine is an amino acid that occurs naturally with all protein foods. Meats and dairy are especially high in Methionine (as they are higher in protein and thus, all amino acids). Methionine enters the body. Notice that this amino acid contains a methyl group as indicated in the name - METHionine.

At some point, the methionine gets in touch with some energy in the form of ATP and magnesium, and becomes SAMe. SAMe travels throughout the body delivering a methyl group to any number of reactions (at least over 400 identified ones). The methyl group allows other metabolic pathways to "go" or work properly. [We will skip the SAH part of the diagram.]~ So, methionine + ATP/magnesium = SAMe

After SAMe delivers the methyl group, it becomes homocysteine. ~ SAMe minus methyl group = homocysteine.

Homocysteine is ready to accept another methyl group which transforms it back into methionine. ~ homocysteine + methyl = methionineRemember that methionine + ATP/MG = SAMe. And this is how methyl groups are transported throughout the body.

However, if there are not enough methyl groups to add to homocysteine, then the homocysteine levels build-up in the body. This is bad. Very bad. Elevated homocysteine levels are associated with heart disease, poor circulation, degenerative illnesses, and other unpleasant conditions. So we must get homocysteine levels down.

Where can homocysteine get some methyl groups so it can transform into methionine? One pathway is from folate+B12. A different pathway is from TMG (or betaine, DMG). Either of these pathways can give a methyl group to homocysteine. Some people may make better use of one pathway over another so this is why several of these precursors are often recommended together. Choline is another possible methyl donor. MSM MAY be a methyl donor but research has not confirmed this.

An alternate way to keep homocysteine from building up is with B6/magnesium. This is a transsulfation pathway that converts homocysteine to cysteine. ~ Homocysteine + B6/magnesium = cysteine

Some more conversions happen in this pathway including making glutathione and taurine. One step is adding molybdenum and continuing on to convert toxic sulfite molecules to really helpful sulfate molecules. The sulfate then goes throughout the body doing both wonderful building up work, and detoxing harmful chemicals (such as heavy metals and phenols).

Cysteine is real interesting. It is a thiol (meaning it contains sulfur) and its side chain is used on enzymes and it is also responsible for the 3-dimensional stability of enzymes.http://micro.magnet.fsu.edu/aminoacids/pages/cysteine.html

Over-methylator and Under-methylator

The Pfeiffer Treatment Center identifies two different supplement regimes depending on if you are an "over-methylator" or an "under- methylator." These are VERY rough estimations and nothing concrete...they may not be accurate either; further research is needed.

Q: How can you find out if you are over or under?A: Histamine levels may be a good indicator of whether someone is an over or under-methylator.

Low histamine points to over-methylator: If your histamine level is low you are probably an over-methylator (according to Pfeiffer research). This means that many supplements would be detrimental to him (those containing methyl). These would include taurine, GABA [both precursors to methyl activity in the brain], folic acid, B12, B6, DMG, TMG (and SAMe) - to name a few.

Q: What test checks histamine levels?A: There is a blood test to measure histamine. Your pediatrician can do it.

Q: How can I lower the histamine level, and the results of a histamine reaction?A: Some people who have trouble converting sulfur to sulfate (PST issue), and who have a sensitivity to certain foods and chemicals because of this, often times develop a high histamine level. My son develops a runny nose as a reaction to this problem. Benadryl helps my son with this, and anything else that lowers histamine would help him, also. I think the Feingold Diet, No-Fenol, or avoiding certain phenolic and high salicylate foods may help the sulfation problem and subsequently lower the high histamine level. Benadryl and Pepcid AC are histamine blockers. This might explain why Pepcid AC is so effective on some kids. A few parents have reported that a histamine reaction with certain foods did not happen when No-Fenol was given with those foods. MSM or Epsom salts also supply sulfur to the system and may be helpful. Some people cannot convert the sulfur in MSM to the needed sulfate form although other people can. Epsom salts supply sulfur in the sulfate form directly. Taking MSM or Epsom salts may alleviate a histamine reaction.

Q: What amount of B6 is considered "high"?A: From the site http://www.methylmagic.com/faq.htmlSome supplements have lots of B6 (e.g. 100mg) and the author usually aims for between 20 and 50mg per day of B6. Excess niacin (B3) is metabolized by methylation and thus uses up methyl groups. Also aim for 50 mg or less. These values are likely for an adult so a child needs much less.

According to Pfeiffer, "Actually excess niacin (B3) is metabolized by methylation and thus uses up methyl groups." So if you are an over-methylator, meaning you have extra, then B3 is good because it uses them up, but if you are an under-methylator, meaning deficient, then giving extra B3 is bad because it drains an already poor supply.

Frequently Asked Questionshttp://www.methylmagic.com/faq.html

Q: What do we really need for methylation to prevent or treat depression? - vitamins, TMG or SAMe?

A: People need folate, B12, B6, TMG and zinc whether or not they use SAMe. SAMe will not replace all the actions of any of these. All SAMe provides are methyl groups (expensive but also direct and efficient methyl groups), adenosine and methionine. Many people who "need" SAMe actually are low in precursors (e.g. methionine, folate, B12, B6, TMG and zinc). If you take SAMe, these precursors will help you recycle it, and should reduce the amounts of SAMe you need to take. (extra methionine is probably unnecessary as long as you have good protein sources in your diet and as long as your digestion is good).

Also note that for depression several aspects of biochemistry come into play and a depressed person should want to handle all of these. Three key areas:

Q: What about MSM (methyl-sulfonyl-methane) as a methyl donor?A: Despite having looked in the literature, the Methyl Magic manufacturers have not yet found out if MSM acts as a methyl donor. It may be fine and just that no one has done the experiments. Some of MSM's properties may be due to methylation but we just don't know. MSM is apparently a good source of organic sulfur. TMG (betaine) is a good methyl source - TMG works and is inexpensive.

Q: How does high dose niacin (vitamin B3) fit in with methylation?A: Actually excess niacin is metabolized by methylation and thus uses up methyl groups. One source suggests to aim for under 75mg (usually ~50mg) of niacin+niacinamide per day from supplements. If you are taking large quantities of B3, please get your homocysteine and SAM checked to make sure this niacin isn't excessively taxing the methyl metabolism. Likewise some supplements have lots of B6 (e.g. 100mg) and between 20 and 50mg per day of B6, or less, might be better.

Q: Why would someone necessarily be deficient in methylation other than a lack of the proper nutrients? Is there a genetic variation serious enough that a person with sufficient vitamins would still suffer from insufficient methylation?

A: There are genetic variations that make some people especially deficient or "slow methylators". There are several kinds of such people and variations i.e. several genes and the enzymes they produce that can be inefficient or even missing altogether. In extreme cases these can cause homocysteinuria. Usually these can be handled with a combination of folic acid, B12, B6 and TMG. With some, but not all of these variations, extra amounts of the cofactor (e.g. folate) will compensate for the inefficient enzyme. Other times you need to rely on the other pathways e.g. TMG, and B6 pathways when the folate+B12 pathway is missing. Today we know that zinc should also be in this supplement combination. For people with these more serious deficiencies very high levels of folic acid (e.g. 5 milligrams/day) and TMG (e.g. 6 grams/day) are usually needed. There are some types of genetic deficiencies where SAMe is the specific needed supplement although these are less common (according to conventional wisdom) than those needing B6, folic acid, TMG etc.

Contradiction with information from Pfeiffer Treatment Center

There is a contradiction between the majority of the information on methylation and the description on the Pfeiffer Treatment Center web site. The precursors that go into the methylation cycle for SAMe/neurotransmitters/dopamine/serotonin are methionine, folate, B12, B6, TMG and zinc, and maybe some calcium and magnesium.

So, logic follows that if the one of the precursors is limiting (low), then methylation would be limiting (low) and the neurotransmitters and resulting pathways would be limited (low). This also supports the use of SAMe and the precursors as being effective for depression (because they increase neurotransmitters which improve mood).

But the Pfeiffer information does not follow this. From the Pfeiffer site http://www.hriptc.org/BioTreatment.html in regards to depression and neurotransmitters, one sentence says: "Over- Methylation: Many persons who suffer from anxiety and depression are over-methylated which results in excessive levels of dopamine, norepinephrine and serotonin."

Over-methylation would result in excessive levels of the neurotransmitters listed, but this is not necessarily consistent with depression (I don't know about anxiety). The other references say that under-methylation results in depression.

The next sentence from Pfeiffer says:"Typical symptoms include chemical and food sensitivities, underachievement, upper body pain, and an adverse reaction to serotonin-enhancing substances such as Prozac, Paxil, Zoloft, St. John's Wort, and SAMe."

It would seem that over-methylation would be adversely affected by MORE serotonin, SAMe, etc, because the body already has too much of that stuff. However, I could also associate the food sensitivities and underachievement with depression.

Continuing with Pfeiffer: "They have a genetic tendency to be very depressed in folates, niacin, and Vitamin B-12, and biochemical treatment focuses on supplementation of these nutrients."

This part is the opposite of other references. The folates and vitamin B-12 would be precursors, so an over-methylator should not be deficient in precursors. A person deficient in precursors should be low in methylation. Pfeiffer may have different information...or it may be more complicated and the short summary on their web site is not conveying things right. So, either something is missing, one of these is not quite right, or something else is going on, but at least this explains the inconsistency between Pfeiffer and other sources.

Pfeiffer is saying that B6, TMG, DMG, SAMe and SSRIs (medications that increase serotonin such as Zoloft and Prozac) are good for those with low methylation, but B12 and folic acid is not (even though folic acid and B12 are precursors too). However, the other sites say that ALL of those nutrients listed are precursors or otherwise aid in increasing methylation. Pfeiffer is splitting out the folic acid and B12 from the others for some reason. Andy Cutler made a comment at one point saying that Pfeiffer may be using these terms differently and may be referring to specific aspects of the methylation cycle

I called the Pfeiffer office and the answer was that they would be happy to answer the methylation question and discuss it for $90. I explained the situation, and the receptionist said no problem, but it would cost $90 up front. If someone is currently a patient of Pfeiffer, then maybe they could ask at their next visit or conference call.

This is the question that needs to be answered by Pfeiffer:"If folate (folic acid) and B12 are two of the precursors (as are B6, TMG, and maybe zinc, magnesium and calcium) why would a deficiency of folate and B12 indicate OVER-methylation. Wouldn't a deficiency of the precursors also mean a deficiency of the end products or low/under methylation?"

So what does this have to do with enzymes or autism conditions/neurology?

If you are GFCF this probably becomes much more of a concern because you loose primary sources of the B vitamins including folate and B12, amino acids and minerals; then you get into adding all that stuff back in individually as supplements. By taking enzymes, you can eat the whole grains and dairy which are excellent sources of those things plus anything you eat will likely be better digested and absorbed with enzymes. So you get more actual nutrition from your food and any supplements you take. This is not about some mythical function but taking advantage of rate limiting processes and providing a nutrient that removes the rate limit. There is quite high B12 in milk. If you have an injured gut by any means, you sharply reduce your ability to absorb B12. If you go grain and dairy free in addition to this, you are very likely to be B12 deficient.

This explains why some people do so much better on enzymes as well. Enzymes are supplying better nutrition and correcting multiple pathway hurdles throughout the body all at the same time. Many of the treatments and supplements recommended to those with autism conditions are targeted to one pathway at a time, or aim to correct a pathway by supplying all the needed precursors individually.

One technique of giving high doses of taurine (as done by Dr. Bradstreet) has an effect of improving digestion. Taurine is needed in bile production…bile improves fat digestion and digestion in general. If you take enzymes to do this digestion, then you are more directly accomplishing the same thing as the taurine supplementation. You also get the added bonus of improving all nutrient uptake at the same time, including better uptake of taurine from food. So you improve the faulty pathway in both directions.

Other commonly suggested supplements include NAC (cysteine), glutathione, molybdenum, sulfur/sulfate, melatonin, and serotonin. If you can get the methylation working properly, you may not need to add in all these components separately. The melatonin and serotonin come from SAMe function. Too much B6 may deplete this. Having a good source of methyl groups plus methionine in the diet is a good way to improve serotonin and melatonin supplies.

Why do we see the constant trend of people with phenol intolerances having bad reactions to high B6 supplements?

This seems to go back to the methylation cycle. If you look at the diagram at the link given above, you see that B6/magnesium converts homocysteine to cysteine. However, in order for the cysteine to be converted on you need sulfation to be working properly. Those with faulty sulfation processes are not able to do this well and too much cysteine accumulates. Cysteine has excitatory properties and can even be toxic in high amounts. So supplying B6 increases the cysteine supply where it gets stuck in the pathway and accumulates.

This also explains why if someone did okay with high B6 or even TMG and then started enzymes, they may start to see problems with those supplements over time. Or if they take enzymes and go off a GFCF diet (thereby adding in more B vitamins). The enzyme therapy is adding in more B vitamins, so now there is a greater supply of B6. The increase in B6 "pulls" the methylation cycle into producing more cysteine…maybe too much cysteine accumulates. So ending the high B vitamins lets this cycle settle into a more balanced state. The high cysteine levels are reduced and the adverse reactions subside. Someone may be very well on a "regular" recommended daily allowance of B6, but only sees adverse reactions at the higher doses.

Here are some links that explain the problems with too much cysteine.http://www.cfsn.com/sulph.htmlhttp://www.mercola.com/1999/apr/4/secretin_autism.htmhttp://www.mercola.com/1999/apr/11/l_cysteine_for_autism_caution.htm

What is the health risk of too much vitamin B6 ? Too much vitamin B6 can result in nerve damage to the arms and legs. This neuropathy is usually related to high intake of vitamin B6 from supplements, (28) and is reversible when supplementation is stopped. According to the Institute of Medicine, "Several reports show sensory neuropathy at doses lower than 500 mg per day". As previously mentioned, the Food and Nutrition Board of the Institute of Medicine has established an upper tolerable intake level (UL) for vitamin B6 of 100 mg per day for all adults. "As intake increases above the UL, the risk of adverse effects increases." [Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press. Washington, DC, 1998. ]http://www.cc.nih.gov/ccc/supplements/vitb6.html#risk

How does mercury toxicity affect methylation?

Mercury toxicity may disrupt this cycle making it practically unsolvable until the metals are removed.

Mercury is highly attracted to sulfur. If there is mercury floating around, it will gravitate to sulfur compounds and tie them up. Any or all of the sulfur reactions will be faulty, and it will be hard to fix unless (or until) you remove the mercury or other metals. If you are mercury toxic and you do anything to increase methylation, you may increase cysteine. So if a child responds badly to high B6, mercury toxicity is a possibility because it more directly increases cysteine. Instead of this increase being beneficial, it may very likely attract mercury, and thus increase mercury movement and cause further damage…so you just can't win. You need to increase the sulfur compounds to detox the mercury (and other things), but these same sulfur compounds also start to float the mercury and cause worse problems as it moves around....

One interpretation is if you respond well to B6 and possibly TMG then you may be an under-methylator and may not have severe mercury toxicity. This is what cysteine is about, if you are severely mercury toxic then you are caught since you need more cysteine to function since the mercury takes it out, but if you have more cysteine you mobilize the mercury and you get more doing damage.

Mercury is involved in defeating so many pathways. Mercury may lead to the problems with phenol intolerance too. The mercury disrupts the cysteine pathway, so sulfate is limited and is not supplied for detoxing the phenol compounds (or other compounds).

Selenium binds with mercury and parks it in the liver in an insoluble form, as well as aiding the manufacture of glutathione which is a mercury detox pathway. So by adding Selenium you may start making some ground in correcting the pathways. So selenium gives a lot of effect for minimal hassle provided you don't take too much. Look for the selenomethionine form (a source of selenium and methionine). This is not chelation but may help while you are looking at chelation or in the process of chelating.

This methylation stuff may be more complex than is obvious. It is an intertwined process. Remember also that amino acids such as tryptophan and tyrosine may be involved in this more directly. I don't know what the relationship is between the levels of methylation and amino acids, but that may outweigh all this other stuff. Biochemistry gets very complex very rapidly.

About B12 and Increasing Methylation

There is a "newer" interest in vitamin B12. This is supplemented in two forms. One is called Cyanocobalamin. The other is Methylcobalamin and is the methylated, coenzyme form of B-12 (cobalamin) active in the brain and central nervous system. The cyanocobalamin form needs to be converted to the methylcobalamin form, so the latter is preferable if possible. B12 is needed to work with folate (folic acid or vitamin B9). B6, B12, and folate have a synergistic effect when given together. The B12 working with the others is needed for good nervous system working and myelin integrity. High folate levels or taking high amounts of folate without B12 can mask a B12 deficiency. There is lots of information by doing a search for B12. The following is from the Vitamin Research Products site:

"Recently a flurry of interesting articles from the medical newswires and lay press have focused on B vitamins--specifically vitamins B6, B12, and folic acid. Some articles are simple reiterations of research from the past. Methyl Caps includes vitamin B6, B12, folic acid, and betaine (trimethylglycine). VRP was one of the first supplement companies to recognize the damaging effects of high levels of homocysteine, and how homocysteine could be easily controlled by the simple nutrients found in Methyl Caps." [Provocative New Findings on Vitamins B6, B12 and Folic Acid Link Discovered Between Homocysteine, Alzheimer's and Diabetes]

Besides just trying to supplement the individual precursors to increase methylation, there are a few products just for increasing methylation. They contain most of the precursors (a couple listed below). Most of the sites suggested adding the precursors rather than the SAMe or methionine as being a good corrective measure. I thought the ratios of B6 to B12 were interesting - the B6 is usually quite under 25 mg:http://www.integrisnutrition.com/methylate.shtmlhttp://www.gaines.com/html/Source/SN1038info.htmlhttp://www.gaines.com/html/product_info/ARG/ARG72580info.html

Here are the ingredients of Methyl Caps sold by www.vrp.comName: Methyl Caps, 180 capsules

What is a 'good' amount of B12 versus a therapeutic amount. Some companies sell B12 supplements in amounts up to 1000 mcg even though the RDA value is between 2 and 6 mcg/day for an adult. That is quite a range!

"Vitamin B12, plays an important role in the metabolism of nerve tissue, protein, fats and carbohydrates. It also aids in the production of DNA/RNA and red blood cells. It also plays a role in the health of the spinal cord. A lack of adequate levels of Vitamin B12 may lead to pernicious anemia, lack of energy, weakness, muscle soreness, mental and nervous disorders, poor reflexes, speaking difficulty and nerve degeneration. As a dietary supplement, take one lozenge 1 to 2 times daily by holding under the tongue until dissolved."

Of course there were much lower strengths of B12 too. This was at a site called GreenCanyon.com that had lots of name brand supplements discounted by 20% or more.

Some other places said that those most likely to be deficient in B12 are those "Individuals with stomach and small intestinal disorders may not absorb enough vitamin B12 from food to maintain healthy body stores" Also, vitamin B12 can not be manufactured by any plants, and therefore is only found in animal products. So, vegetarians may not consume dairy products or meat which are good sources of B12, and they need to take care not to become deficient. Older people are also likely to become deficient. B12 is getting more recent press because of how it might aid in Alzheimers. Fortified breakfast cereals or foods were suggested for vegetarians or older people. There are sublingual dots you can buy too as well as in other supplements. (one place to read quick summaries about vitamins is www.anyvitamins.com)

B12 does not come from plants, only animal products. Strict vegetarians need to be aware of this and supplement it. B12 is stored in the liver and a few other spots. B12 toxicity is very hard to achieve and the main problems have been associated with B12 injections. This has even been attributed to some of the "other stuff" in the injection and may not be the B12. Or there are a few rare conditions that the injections may be contraindicated for.

B12 is released from proteins by stomach acid and digestion. Older people and those with low stomach acid or faulty digestion may develop B12 deficiencies (along with other nutrient deficiencies) because of this. Enzymes, particularly the proteases, digest the proteins and may make more B12 available (along with other nutrients). If you take anything that inhibits digestion or stomach acid, then you are inhibiting B12 release and absorbtion: like calcium carbonate with meals, Tums, Rolaids, and certain medications which affect stomach acid.

B12 combines with something called Intrinsic Factor in order to work. The stomach acid issues can affect the Intrinsic Factor availability too.

B12 is absorbed in the ileum, the very last part of the small intestine. Most everything else is absorbed before that in earlier parts of the intestine. For this reason, people with colon problems may be B12 deficient but not as deficient in other nutrients because the ileum is followed by the colon (so when problems "backup" from the colon into the small intestine, the B12 is affected first).

B12 may be deficient in people with injured guts because something called Intrinsic Factor is necessary to bind with the B12 in the stomach to "protect" it in the upper small intestine and from the stomach acid. Then the Intrinsic Factor attaches to some receptors at the end of the small intestine in the ileum aiding the B12 uptake. So at times it is the Intrinsic Factor and the fact it cannot attach to the receptors to facilitate transport and absorption into the body that is the problem and the cause of B12 deficiency. The sublingual B12 is highly preferred for this reason because it gets the B12 into the system and bypasses the entire Intrinsic Factor mechanism.

B12 deficiency can affect the nerves (as other nutrients can). The recent popular idea of getting more folic acid in the diet can mask a B12 problem, and too much folic acid (over 800 mcg a day for an adult) can lead to B12 deficiency if it is not in balance. So when people read folic acid is necessary and run out and start wolfing down folic acid without balancing it, this can provoke a B12 deficiency.

B12 is needed in incredibly small amounts like 2-6 mcg a day for an adult, kids need less. However, the therapeutic amount is between 100-1000 or more mcg a day for an adult for a couple of months. When the therapeutic amount should be used is open for debate with no clear cut evidence except for pernicious anemia (which is chronic B12 deficiency). The Alzheimers, MS, AIDS, etc issues are speculative at the moment. Some people say it may help, but others say not.

So it appears to me that healing the gut, taking enzymes (particularly proteases), and eating at least some animal foods go a long way to resolving this issue. Additional B12 for awhile may be helpful - a "try it and see" sort of thing - for mental and nerve function. Give at least a little bit of other Bs and folic acid along with it.

Here are a few more easier to understand yet thorough explanations. One has a picture of how B12 and folic acid affect the cycle of methylation, and B6 acts on another part. The precursors are much cheaper than the SAMe. It says that methylation is enhanced by estrogen and this may point to gender differences....anyway, more to explore.

Here is a link on the interrelationships of these things. It gives different amounts of B12 and folate for increasing methylation:http://www.miami-dade-online.com/MethylManual2.htmhttp://www.miami-dade-online.com/MethylManual1.htm

This one mentions that one form of B12 may be more effective than another:http://www.lef.org/magazine/mag2001/jan2001_qanda.html

Part 2: HistamineI spent a ton of time looking into this. Here are some of the results. Please take all of this in context of everything else, these biochemical reactions are all intertwined and complex.

I was wondering WHY would histamine levels tell you about methylation function?

Methionine is a methyl carrying amino acid + ATP/magnesium = SAMe. SAMe goes throughout the body delivering methyl groups to over 400 different reactions.

One way histamine is de-activated (eliminated) is by receiving a methyl group from SAMe. So if there is low methylation, there is low SAMe, and the histamine levels are higher because of the lack of methyl groups to deactivate it. If there is high methylation, there is higher amounts of SAMe, and lots of histamine can be deactivated.

Where does this histamine come from?One source is when the amino acid histidine looses a carboxyl group. Some bacteria can faciliate this conversion too. So if you have a bacteria overgrowth, it may be using up histidine and converting it to more histamine. Another big source is directly from foods. Some people may have a problem eliminating histamine from their foods and this causes reactions which LOOK LIKE allergies, but are not true IgE mediated allergies. You may see a histamine reaction which is just too high levels of histamine and not because an antigen caused an immune reaction to something.

What are histamine containing foods?Here is a great site on what foods contain what chemicals. The first link tells about "histamine intolerance" and amine foods:http://users.bigpond.net.au/allergydietitian

Notice that many of the foods are often considered "phenol" foods even though they are not high in salicylates or phenols. They are high in amines/histamine. There are also foods that trigger a histamine reaction. This means that they directly cause a release of histamine - in some people, this includes the natural salicylates or other common additives:Egg, strawberries, cocoa, chocolate, bananas, citrus, pineapple, pork, soy, benzoates, sulfites, nitrates, BHA, BHT, food colors, MSG.

The similarity with this and the Feingold program is very interesting.

If someone has low methylation (maybe B12 deficiency or metal interference, etc.) then you may have high histamine levels and a problem eliminating the additional histamine from foods. You would also have more chemical running around in the body triggering histamine reactions.

What lowers histamine?Taking an antihistamine is one way. Antihistamines typically work by either inhibiting the release of histamine (like during an immune reaction) or blocking the uptake of histamine (like from food). Magnesium and vitamin C are natural anti-histamines. Vitamin C can destroy histamine directly. This is why these supplements are recommended when you are sick for any reason.

Another way to reduce histamine levels is to supply antioxidants. Free radicals are produced from both external sources and internal natural biochemical reactions. Too many free radicals provoke histamine reactions. Natural "phenols" in foods such as polyphenols, flavenoids, bioflavenoids, beta-caroteine and all those other things that No-Fenol appears to make more available to the body act as antihistamines. These natural phenols are also the trendy "antioxidants" for eliminating free radicals in the body which many places are advertising now. They neutralize the free radicals which cause histamine reactions. Less free radicals, less histamine reaction. These phenols coming from the fruits and vegetables lower histamine by 2 or 3 different mechanisms. Again, it gets complicated and there is no ONE definitive pathway.

Salicylates occur in most foods as a mean to "protect" the plant from injury. When the surface of the fruit is damaged (disease, injury, bugs, something taking a bite out of it), the food comes into contact with oxygen, and starts to break down via oxidation. The salicylates/phenol in the food are an anti-oxidant which preserves the food. This is why if you take a bite out of an apple, the "bite-mark" starts to turn brown. The apple is ttempting to heal the injury like applying a bandaid and slow or stop the rotting oxidation.

Remember that "phenols" are a huge category of compounds. Some are beneficial from natural foods, but others may be a problem. Saying something has "phenol" is like saying something contains "nitrogen". It could be anything.

A main mechanism of lowering histamine is by an enzyme produced in the gut mucosa. So if you have an injured gut for whatever reason, less enzyme may be produced, and this may mean you have a lower ability to eliminate histamine (especially from food sources). If you have multiple chemical allergies, you may want to consider a "histamine intolerance" or that you have histamine levels that run high. Inability to get rid of too much histamine would make you reactive to many foods, and overreactive to many things in the environment. Common additives such as artificial colorings, sulfites, BHA, BHT, benzoates, etc, can all inhibit this histamine degrading enzyme. Another way these can be problematic.see Feingold Program

What does histamine do?Histamine is located throughout the entire body. In many instances, it causes inflammation, runny nose, itching, hives, sore throat, coughing, flushing, headache and all those other typical allergy reactions. In the gut, it signals the production of gastric acid. This is why some remedies for acid stomach are really antihistamines. In the brain, it functions like a neurotransmitter. A couple of functions include affecting hunger or feeding, and also sleep/wake cycles (the circadian rhythm). A bit more histamine keeps you awake, and lower histamine levels help you sleep. This is why many antihistamines make you drowsy. Some newer antihistamines have been developed to get around this issue.

http://www.thedietdoctor.com/incl/571.cfmThe role of antioxidants in the immune system is multifaceted as they can serve to either suppress or enhance the immune response. Depending on the desired response, different antioxidants can play different roles in balancing the immune response effectively in an individual. Beta-carotene, selenium, vitamin C, and vitamin E are all examples of exogenous antioxidants. In addition to these that come from our diet, the body also has a system of enzymes, which form the endogenous antioxidants. Together, they work to eliminate free radicals from the body.

As andrew pointed out, if the immune system is under-reactive, this is a problem, but if it is over-reactive it is a problem. People may have any assortment of these things going on at a time.

Yes I've read that before and it makes it all even less convincing or believable. Antihistamines lower anxiety for me because they knock me out. Is that what a "good response" is?

Niacin acts like valium or a benzodiazepine in the brain (it's inhibitory-slows thinking). These are bad for OCD why? Valium was designed using b3 as a model.

Over the years I have been labeled with different "disorders". For instance I no longer am labeled OCD. These "disorders" are literally made up by society and pharmaceutical companies. They aren't real things. Even if many people fit a certain group of characteristics, there still is no such REAL thing as OCD or schizophrenia... like a table or chair is a real thing. These are just concepts, and useful to some at best.

I say just go with what you're suggesting and try stuff. That's all a psychiatrist does anyway. Don't get caught up in the labels and concepts because you will never "figure it out" so to speak. Just like we know more about hair loss now, we haven't figured any ONE thing out as the cause. We just find ever more complex interactions in the body, and instead of becoming simpler it gets much more advanced. The more we understand, the more questions arise.

Paradox wrote:Yes I've read that before and it makes it all even less convincing or believable. Antihistamines lower anxiety for me because they knock me out. Is that what a "good response" is?

Niacin acts like valium or a benzodiazepine in the brain (it's inhibitory-slows thinking). These are bad for OCD why? Valium was designed using b3 as a model.

Over the years I have been labeled with different "disorders". For instance I no longer am labeled OCD. These "disorders" are literally made up by society and pharmaceutical companies. They aren't real things. Even if many people fit a certain group of characteristics, there still is no such REAL thing as OCD or schizophrenia... like a table or chair is a real thing. These are just concepts, and useful to some at best.

I say just go with what you're suggesting and try stuff. That's all a psychiatrist does anyway. Don't get caught up in the labels and concepts because you will never "figure it out" so to speak. Just like we know more about hair loss now, we haven't figured any ONE thing out as the cause. We just find ever more complex interactions in the body, and instead of becoming simpler it gets much more advanced. The more we understand, the more questions arise.

Yes anti-histamines like mirtazapine knocked me out--some of the best sleep that I have gotten in years on that stuff, and I have bad insomnia, but not sure if it has other mechanisms that induce the sleep. It also reduced anxiety greatly. I was on effexor, which I believe has anti-histamine actions (need to confirm this though), anyways it really reduced anxiety, but that could be due to serotonin reuptake inhibition.

Not sure if there is a difference in niacin and niacinamide using methyl groups, but I think it is niacinamide that is known for it's valium like effects and not niacin. I read that plain nicotinic acid at a dosage of 50mg can be used to check histamine levels. Supposedly if you flush at 50mg on an empty stomach then histamine is high. Niacin does increase histamine, and if it uses methyl groups then it does support the relationship between under methylation and high histamine. How it relates to "OCD"? I don't know.

I still don't know a whole lot about this and yes it is confusing. I will experiment and see what I can find out.

I realize that you posted this thread a while back and that you have probably moved on. Thanks for your time though. I'll let you know if I learn anything substantial.

I don't mean to be discouraging if it comes off that way. I still think that there is truth in it, but I just wasn't able to get to any concrete conclusions personally. Definitely let me know if you have any luck.

I'm bumping this thread back up because I think it's really important, and for some people absolutely life enhancing to say the least. Generally, I think most of the people on this forum would benefit from some mood lifting and I want to get some feedback from users like Beebrox and others who went through self trial and error with different methylation and mineral protocols to generate a more precise overall picture. In all honesty, I think getting this department to optimal function is the only way of living for some people, because if it's imbalanced it affects how you experience every single moment of the day, I think for a lot of people that this right here is one of the must have pillars, bases, windows, however you want to call it, to build yourself and your life back up.

The topics I want to mainly discuss are:

diet for insulin control and how much can it help with mood/disordersenhancing methylation in a bioindividual manner, how much do we know now about what exactly does a specific person needmental/emotional freedom and how much is it really a freedom? It seems to me that people who have sensitive methylation pathways shouldn't resort to always "listening to intuition" as something clearly isn't working right. We want to understand this and optimize it.probiotics and rebuilding the gut integrityundenatured whey and boosting glutathione in the body/detoxification , when is it a concern for causing a methyl trap and when does it provide big benefits

Appart from everything you can do biochemically, it's always as important to be mindfull at least few times a week, to reduce stress and de-attach concepts from thoughts and thoughts from emotions. But unless there is this inner intuitive drive (methylation is a big thing here) life is going to be and feel mechanical and with not much sense or purpose, fixing this is an absolute must imo. The sooner the better.

When and how exactly do you know that you've "leveled" out properly and optimally, as it seems that something can always function better. How to prevent this loop of neverending thinking how to optimize your metabolism?

Things like the active B-complex, B6,B9,B12, zinc, magnesium, calcium, copper, vitamin D, potassium, omega 3's, all seem to play a major role. How to find the right combination for this since most people actually don't fall into a clear cut over or under / methylation group. Bioindividuality is the word here, so how to find and assess the situation properly?